tbuckley/cabot-search huggingface dataset:
Points to consider: EULAR–UEMS standards for the training of European rheumatologists
Authors: Alessia Alunno, Tadej Avcin, Catherine Haines, Sofia Ramiro, Francisca Sivera, Sara Badreh, Xenofon Baraliakos, Johannes W J Bijlsma, Frank Buttgereit, Kaushik Chaudhuri, Jose A P Da Silva, Jean Dudler, Ricardo J O Ferreira, Tania Gudu, Eric Hachulla, Mette Holland-Fischer, Annamaria Iagnocco, Tue Wenzel Kragstrup, György Nagy, Vasco C Romão, Simon R Stones, Marloes van Onna, Christopher J Edwards
Journal: Annals of the Rheumatic Diseases (2023)

Postgraduate rheumatology training programmes are already established at a national level in most European countries. However, previous work has highlighted a substantial level of heterogeneity in the organisation and, in part, content of programmes.To define competences and standards of knowledge, skills and professional behaviours required for the training of rheumatologists.A European Alliance of Associations for Rheumatology (EULAR) task force (TF) of 23 experts, including two members of the European Union of Medical Specialists (UEMS) section of rheumatology, was convened. The mapping phase consisted of the retrieval of key documents on specialty training in rheumatology and other related specialties across a broad set of international sources. The content of these documents was extracted and represented the foundation for the document draft that underwent several rounds of online discussion within the TF, and afterwards was also distributed to a broad group of stakeholders for collecting feedback. The list of generated competences was voted on during the TF meetings, while the level of agreement (LoA) with each statement was established by anonymous online voting.A total of 132 international training curricula were retrieved and extracted. In addition to the TF members, 253 stakeholders commented and voted on the competences through an online anonymous survey. The TF developed (1) an overarching framework indicating the areas that should be addressed during training, (2) 7 domains defining broad areas that rheumatology trainees should master by the end of the training programme, (3) 8 core themes defining the nuances of each domain and (4) 28 competences that trainees should acquire to cover each of the areas outlined in the overarching framework. A high LoA was achieved for all competences.These points to consider for EULAR-UEMS standards for the training of European rheumatologists are now defined. Their dissemination and use can hopefully contribute to harmonising training across European countries.
A Selective Bottleneck During Host Entry Drives the Evolution of New Legume Symbionts
Authors: Ginaini Grazielli Doin de Moura, Saida Mouffok, Nil Gaudu, Anne-Claire Cazalé, Marine Milhes, Tabatha Bulach, Sophie Valière, David Roche, Jean-Baptiste Ferdy, Catherine Masson-Boivin, Delphine Capela, Philippe Remigi
Journal: Molecular Biology and Evolution (2023)

Abstract During the emergence of new host–microbe symbioses, microbial fitness results from the ability to complete the different steps of symbiotic life cycles, where each step imposes specific selective pressures. However, the relative contribution of these different selective pressures to the adaptive trajectories of microbial symbionts is still poorly known. Here, we characterized the dynamics of phenotypic adaptation to a simplified symbiotic life cycle during the experimental evolution of a plant pathogenic bacterium into a legume symbiont. We observed that fast adaptation was predominantly explained by improved competitiveness for host entry, which outweighed adaptation to within-host proliferation. Whole-population sequencing of bacteria at regular time intervals along this evolution experiment revealed the continuous accumulation of new mutations (fuelled by a transient hypermutagenesis phase occurring at each cycle before host entry, a phenomenon described in previous work) and sequential sweeps of cohorts of mutations with similar temporal trajectories. The identification of adaptive mutations within the fixed mutational cohorts showed that several adaptive mutations can co-occur in the same cohort. Moreover, all adaptive mutations improved competitiveness for host entry, while only a subset of those also improved within-host proliferation. Computer simulations predict that this effect emerges from the presence of a strong selective bottleneck at host entry occurring before within-host proliferation and just after the hypermutagenesis phase in the rhizosphere. Together, these results show how selective bottlenecks can alter the relative influence of selective pressures acting during bacterial adaptation to multistep infection processes.
SIRT2 regulates extracellular vesicle-mediated liver–bone communication
Authors: Longshuai Lin, Zengya Guo, Enjun He, Xidai Long, Difei Wang, Yingting Zhang, Weihong Guo, Qian Wei, Wei He, Wanying Wu, Jingchi Li, Lulu Wo, Dengli Hong, Junke Zheng, Ming He, Qinghua Zhao
Journal: Nature Metabolism (2023)

Abstract The interplay between liver and bone metabolism remains largely uncharacterized. Here, we uncover a mechanism of liver-bone crosstalk regulated by hepatocyte SIRT2. We demonstrate that hepatocyte SIRT2 expression is increased in aged mice and elderly humans. Liver-specific SIRT2 deficiency inhibits osteoclastogenesis and alleviates bone loss in mouse models of osteoporosis. We identify leucine-rich α-2-glycoprotein 1 (LRG1) as a functional cargo in hepatocyte-derived small extracellular vesicles (sEVs). In SIRT2-deficient hepatocytes, LRG1 levels in sEVs are upregulated, leading to increased transfer of LRG1 to bone-marrow-derived monocytes (BMDMs), and in turn, to inhibition of osteoclast differentiation via reduced nuclear translocation of NF-κB p65. Treatment with sEVs carrying high levels of LRG1 inhibits osteoclast differentiation in human BMDMs and in mice with osteoporosis, resulting in attenuated bone loss in mice. Furthermore, the plasma level of sEVs carrying LRG1 is positively correlated with bone mineral density in humans. Thus, drugs targeting hepatocyte-osteoclast communication may constitute a promising therapeutic strategy for primary osteoporosis.
Early alterations in the MCH system link aberrant neuronal activity and sleep disturbances in a mouse model of Alzheimer’s disease
Authors: Sara Calafate, Gökhan Özturan, Nicola Thrupp, Jeroen Vanderlinden, Luísa Santa-Marinha, Rafaela Morais-Ribeiro, Antonella Ruggiero, Ivan Bozic, Thomas Rusterholz, Blanca Lorente-Echeverría, Marcelo Dias, Wei-Ting Chen, Mark Fiers, Ashley Lu, Ine Vlaeminck, Eline Creemers, Katleen Craessaerts, Joris Vandenbempt, Luuk van Boekholdt, Suresh Poovathingal, Kristofer Davie, Dietmar Rudolf Thal, Keimpe Wierda, Tiago Gil Oliveira, Inna Slutsky, Antoine Adamantidis, Bart De Strooper, Joris de Wit
Journal: Nature Neuroscience (2023)

Abstract Early Alzheimer’s disease (AD) is associated with hippocampal hyperactivity and decreased sleep quality. Here we show that homeostatic mechanisms transiently counteract the increased excitatory drive to CA1 neurons in App NL-G-F mice, but that this mechanism fails in older mice. Spatial transcriptomics analysis identifies Pmch as part of the adaptive response in App NL-G-F mice. Pmch encodes melanin-concentrating hormone (MCH), which is produced in sleep–active lateral hypothalamic neurons that project to CA1 and modulate memory. We show that MCH downregulates synaptic transmission, modulates firing rate homeostasis in hippocampal neurons and reverses the increased excitatory drive to CA1 neurons in App NL-G-F mice. App NL-G-F mice spend less time in rapid eye movement (REM) sleep. App NL-G-F mice and individuals with AD show progressive changes in morphology of CA1-projecting MCH axons. Our findings identify the MCH system as vulnerable in early AD and suggest that impaired MCH-system function contributes to aberrant excitatory drive and sleep defects, which can compromise hippocampus-dependent functions.
Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man
Authors: Francisco Lopera, Claudia Marino, Anita S. Chandrahas, Michael O’Hare, Nelson David Villalba-Moreno, David Aguillon, Ana Baena, Justin S. Sanchez, Clara Vila-Castelar, Liliana Ramirez Gomez, Natalia Chmielewska, Gabriel M. Oliveira, Jessica Lisa Littau, Kristin Hartmann, Kyungeun Park, Susanne Krasemann, Markus Glatzel, Dorothee Schoemaker, Lucia Gonzalez-Buendia, Santiago Delgado-Tirado, Said Arevalo-Alquichire, Kahira L. Saez-Torres, Dhanesh Amarnani, Leo A. Kim, Randall C. Mazzarino, Harper Gordon, Yamile Bocanegra, Andres Villegas, Xiaowu Gai, Moiz Bootwalla, Jianling Ji, Lishuang Shen, Kenneth S. Kosik, Yi Su, Yinghua Chen, Aaron Schultz, Reisa A. Sperling, Keith Johnson, Eric M. Reiman, Diego Sepulveda-Falla, Joseph F. Arboleda-Velasquez, Yakeel T. Quiroz
Journal: Nature Medicine (2023)

Abstract We characterized the world’s second case with ascertained extreme resilience to autosomal dominant Alzheimer’s disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for the APOE3 Christchurch ( APOECh ) variant allowed us to discern common features. The male remained cognitively intact until 67 years of age despite carrying a PSEN1 -E280A mutation. Like the APOECh carrier, he had extremely elevated amyloid plaque burden and limited entorhinal Tau tangle burden. He did not carry the APOECh variant but was heterozygous for a rare variant in RELN (H3447R, termed COLBOS after the Colombia–Boston biomarker research study), a ligand that like apolipoprotein E binds to the VLDLr and APOEr2 receptors. RELN-COLBOS is a gain-of-function variant showing stronger ability to activate its canonical protein target Dab1 and reduce human Tau phosphorylation in a knockin mouse. A genetic variant in a case protected from ADAD suggests a role for RELN signaling in resilience to dementia.
Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial
Authors: Farshad Nassiri, Vikas Patil, Leeor S. Yefet, Olivia Singh, Jeff Liu, Rachel M. A. Dang, Takafumi N. Yamaguchi, Mariza Daras, Timothy F. Cloughesy, Howard Colman, Priya U. Kumthekar, Clark C. Chen, Robert Aiken, Morris D. Groves, Shirley S. Ong, Rohan Ramakrishna, Michael A. Vogelbaum, Simon Khagi, Thomas Kaley, Jason M. Melear, David M. Peereboom, Analiz Rodriguez, Maxim Yankelevich, Suresh G. Nair, Vinay K. Puduvalli, Kenneth Aldape, Andrew Gao, Álvaro López-Janeiro, Carlos E. de Andrea, Marta M. Alonso, Paul Boutros, Joan Robbins, Warren P. Mason, Adam M. Sonabend, Roger Stupp, Juan Fueyo, Candelaria Gomez-Manzano, Frederick F. Lang, Gelareh Zadeh
Journal: Nature Medicine (2023)

Abstract Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2–20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1–69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7–13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05–0.87). A total of 56.2% (95% CI 41.1–70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).
RUNX1 mutation has no prognostic significance in paediatric AML: a retrospective study of the AML-BFM study group
Authors: Stephanie Sendker, Amani Awada, Sophia Domagalla, Michael Sendker, Eser Orhan, Lina Marie Hoffmeister, Evangelia Antoniou, Naghmeh Niktoreh, Dirk Reinhardt, Nils von Neuhoff, Markus Schneider
Journal: Leukemia (2023)

Abstract In acute myeloid leukaemia (AML) RUNX1 mutation is characterised by certain clinicopathological features with poor prognosis and adverse risk by the European LeukemiaNet recommendation. Though initially considered as provisional category, the recent World Health Organisation (WHO) classification of 2022 removed RUNX1 -mutated AML from the unique entity. However, the significance of RUNX1 mutation in paediatric AML remains unclear. We retrospectively analysed a German cohort of 488 paediatric patients with de novo AML, enroled in the AMLR12 or AMLR17 registry of the AML-BFM Study Group (Essen, Germany). A total of 23 paediatric AML patients (4.7%) harboured RUNX1 mutations, 18 of which (78%) had RUNX1 mutation at initial diagnosis. RUNX1 mutations were associated with older age, male gender, number of coexisting alterations and presence of FLT3 -ITD but mutually exclusive of KRAS , KIT and NPM1 mutation. RUNX1 mutations did not prognostically impact overall or event-free survival. Response rates did not differ between patients with and without RUNX1 mutations. This comprehensive study, comprising the largest analysis of RUNX1 mutation in a paediatric cohort to date, reveals distinct but not unique clinicopathologic features, with no prognostic significance of RUNX1 -mutated paediatric AML. These results broaden the perspective on the relevance of RUNX1 alterations in leukaemogenesis in AML.
Genomic Profiling of Radiation-Induced Sarcomas Reveals the Immunologic Characteristics and Its Response to Immune Checkpoint Blockade
Authors: Dong-Chun Hong, Jing Yang, Cong Sun, Yuan-Tao Liu, Lu-Jun Shen, Bu-Shu Xu, Yi Que, Xiaojun Xia, Xing Zhang
Journal: Clinical Cancer Research (2023)

Radiation-induced sarcomas (RIS) have a poor prognosis and lack effective treatments. Its genome and tumor microenvironment are not well characterized and need further exploration.Here, we performed whole-exome sequencing (WES) and mRNA sequencing (mRNA-seq) on patients with RIS and primary sarcomas (WES samples 46 vs. 48, mRNA-seq samples 16 vs. 8, mainly in head and neck), investigated the antitumor effect of programmed cell death protein 1 (PD-1) blockade in RIS patient-derived xenograft models, and analyzed clinical data of patients with RIS treated with chemotherapy alone or combined with an anti-PD-1 antibody.Compared with primary sarcomas, RIS manifested different patterns of copy-number variations, a significantly higher number of predicted strong MHC-binding neoantigens, and significantly increased immune cell infiltration. Clinical data showed that the combinatorial use of chemotherapy and PD-1 blockade achieved a higher objective response rate (36.67% vs. 8.00%; P = 0.003), longer overall survival (31.9 months vs. 14.8 months; P = 0.014), and longer progression-free survival (4.7 months vs. 9.5 months; P = 0.032) in patients with RIS compared with single chemotherapy.Elevated genomic instability and higher immune cell infiltrations were found in RIS than in primary sarcomas. Moreover, higher efficacy of chemotherapy plus PD-1 blockade was observed in animal experiments and clinical practice. This evidence indicated the promising application of immune checkpoint inhibitors in the treatment of RIS.
Fetal Cardiac Function at Midgestation in Women Who Subsequently Develop Gestational Diabetes
Authors: Iulia Huluta, Alan Wright, Livia Mihaela Cosma, Karam Hamed, Kypros H. Nicolaides, Marietta Charakida
Journal: JAMA Pediatrics (2023)

Fetuses in women with gestational diabetes (GD) compared with those without GD show evidence of subclinical cardiac functional and morphological changes. However, it is uncertain whether glycemia or the adverse maternal underlying risk factor profile is the main driver for fetal cardiac remodeling.
Efficacy of a Vibrating Crib Mattress to Reduce Pharmacologic Treatment in Opioid-Exposed Newborns
Authors: Elisabeth Bloch-Salisbury, James D. Wilson, Nicolas Rodriguez, Tory Bruch, Lauren McKenna, Matthew Derbin, Barbara Glidden, Didem Ayturk, Sanjay Aurora, Toby Yanowitz, Bruce Barton, Mark Vining, Sue R. Beers, Debra L. Bogen
Journal: JAMA Pediatrics (2023)

Pharmacologic agents are often used to treat newborns with prenatal opioid exposure (POE) despite known adverse effects on neurodevelopment. Alternative nonpharmacological interventions are needed.
GPRC5B protects osteoarthritis by regulation of autophagy signaling
Authors: Liang He, Ziwei Xu, Xin Niu, Rong Li, Fanhua Wang, Yu You, Jingduo Gao, Lei Zhao, Karan M. Shah, Jian Fan, Mingyao Liu, Jian Luo
Journal: Acta Pharmaceutica Sinica B (2023)

Osteoarthritis (OA) is one of the most common chronic diseases in the world. However, current treatment modalities mainly relieve pain and inhibit cartilage degradation, but do not promote cartilage regeneration. In this study, we show that G protein-coupled receptor class C group 5 member B (GPRC5B), an orphan G-protein-couple receptor, not only inhibits cartilage degradation, but also increases cartilage regeneration and thereby is protective against OA. We observed that Gprc5b deficient chondrocytes had an upregulation of cartilage catabolic gene expression, along with downregulation of anabolic genes in vitro. Furthermore, mice deficient in Gprc5b displayed a more severe OA phenotype in the destabilization of the medial meniscus (DMM) induced OA mouse model, with upregulation of cartilage catabolic factors and downregulation of anabolic factors, consistent with our in vitro findings. Overexpression of Gprc5b by lentiviral vectors alleviated the cartilage degeneration in DMM-induced OA mouse model by inhibiting cartilage degradation and promoting regeneration. We also assessed the molecular mechanisms downstream of Gprc5b that may mediate these observed effects and identify the role of protein kinase B (AKT)-mammalian target of rapamycin (mTOR)-autophagy signaling pathway. Thus, we demonstrate an integral role of GPRC5B in OA pathogenesis, and activation of GPRC5B has the potential in preventing the progression of OA.
Characterization of Risk Prediction Models for Acute Kidney Injury
Authors: Yunlin Feng, Amanda Y. Wang, Min Jun, Lei Pu, Steven D. Weisbord, Rinaldo Bellomo, Daqing Hong, Martin Gallagher
Journal: JAMA Network Open (2023)

Importance Despite the expansion of published prediction models for acute kidney injury (AKI), there is little evidence of uptake of these models beyond their local derivation nor data on their association with patient outcomes. Objective To systematically review published AKI prediction models across all clinical subsettings. Data Sources MEDLINE via PubMed (January 1946 to April 2021) and Embase (January 1947 to April 2021) were searched using medical subject headings and text words related to AKI and prediction models. Study Selection All studies that developed a prediction model for AKI, defined as a statistical model with at least 2 predictive variables to estimate future occurrence of AKI, were eligible for inclusion. There was no limitation on study populations or methodological designs. Data Extraction and Synthesis Two authors independently searched the literature, screened the studies, and extracted and analyzed the data following the Preferred Reporting Items for Systematic Review and Meta-analyses guideline. The data were pooled using a random-effects model, with subgroups defined by 4 clinical settings. Between-study heterogeneity was explored using multiple methods, and funnel plot analysis was used to identify publication bias. Main Outcomes and Measures C statistic was used to measure the discrimination of prediction models. Results Of the 6955 studies initially identified through literature searching, 150 studies, with 14.4 million participants, met the inclusion criteria. The study characteristics differed widely in design, population, AKI definition, and model performance assessments. The overall pooled C statistic was 0.80 (95% CI, 0.79-0.81), with pooled C statistics in different clinical subsettings ranging from 0.78 (95% CI, 0.75-0.80) to 0.82 (95% CI, 0.78-0.86). Between-study heterogeneity was high overall and in the different clinical settings (eg, contrast medium–associated AKI: I 2 = 99.9%; P &amp;amp;lt; .001), and multiple methods did not identify any clear sources. A high proportion of models had a high risk of bias (126 [84.4%]) according to the Prediction Model Risk Of Bias Assessment Tool. Conclusions and Relevance In this study, the discrimination of the published AKI prediction models was good, reflected by high C statistics; however, the wide variation in the clinical settings, populations, and predictive variables likely drives the highly heterogenous findings that limit clinical utility. Standardized procedures for development and validation of prediction models are urgently needed.
Errors in Figure 1
Authors: Frederick Green, Zeynep Guller, Suhail Aslam
Journal: JAMA Internal Medicine (2023)

Xuan Wang, MD, PhD; Hao Ma, MD, PhD; Xiang Li, MD, PhD; Yoriko Heianza, RD, PhD; JoAnn E. Manson, MD, DrPH; Oscar H. Franco, MD, PhD; Lu Qi, MD, PhD
Quantitative Assessment of Parent and Patient Preferences
Authors: Ahmed M. Bayoumi
Journal: JAMA Network Open (2023)

Prasanna Ananth, MD, MPH; Meghan Lindsay, MPH; Sophia Mun, MPH; Sarah McCollum, MPH; Veronika Shabanova, PhD; Sophia de Oliveira; Sarah Pitafi, BA; Rebecca Kirch, JD; Xiaomei Ma, PhD; Cary P. Gross, MD; Jackelyn Y. Boyden, PhD, MPH, RN; Chris Feudtner, MD, PhD, MPH; Joanne Wolfe, MD, MPH